Passive tension induced by mechanical stretch is an important growth regulator in skeletal and cardiac muscle. Stretch and the resultant increase in tension stimulates muscle growth while decreased tension from muscle shortening leads to muscle atrophy. The mechanism which couples this physical stimulus to growth or atrophy is unknown. The objective of this project is to study the molecular mechanisms by which passive tension regulates skeletal muscle growth. We will utilize a computerized mechanical cell stimulator device to place tissue cultured avian skeletal myofibers under repetitive passive tensions. This stimulation increases myofiber growth rate and prostaglandin (PG) synthesis, and these PGs are important second messengers for stretch-induced growth of skeletal muscle. Stretch activates phospholipase A2 and D activities which provide arachidonic acid for PG synthesis. Stretch also increases the intracellular activity of prostaglandin synthase (cyclooxygenase). G proteins and protein kinase C are involved in the regulation of stretch- induced PG synthesis in the muscle cells. Our experiments are aimed at determining how stretch activates phospholipase A2, phospholipase D, and cyclooxygenase, and understanding the role of G proteins and protein kinase C in this cascade. We will examine the stretch regulation of cyclooxygenase and G proteins at both the transcriptional and post- transcriptional levels. We intend to identify the "mechanosensor" molecules in the PG second messenger pathway which regulate PG synthesis and skeletal muscle cell growth. The results from these studies will lead to a better understanding of the molecular signaling processes regulating muscle cell growth by tension. This knowledge should lead to the development of new pharmacologic agents to reduce skeletal muscle wasting in patients with limited mobility such as paraplegics and the elderly. It could also lead to new treatments for stretch-induced cardiac hypertrophy.